房颤治疗新型抗凝药物进展课件

房颤新型抗凝药物进展 杨新春首都医科大学附属北京朝阳医院心脏中心 阵发性房颤 持续性房颤 年中风率 房颤与中风 房颤增加中风危险4 5倍中风是非常最常见和灾难性的后果房颤患者全因中风率5 房颤是中风的独立危险因素美国大约15 的中风由房颤引起中风危险随年龄增长无症状房颤患者中风危险同样存在即使是节律控制的患者中风发现同样存在 AFFIRM RACE研究 RACEII RateControlEfficacyinPermanentAtrialFibrillation FusterV etal JAmCollCardiol 2006 48 4 e149 e246 KannelWB etal MedClinNorthAm 2008 92 1 17 42 PageRL etal Circulation 2003 107 8 1141 1145 HartRG etal JAmCollCardiol 2000 35 1 183 187 DulliDA etal Neuroepidemiology 2003 22 2 118 123 低危 中危 高危 1086420 房颤并发脑卒中的机制 血流缓慢 内皮功能障碍及血液的高凝状态等使血液易发生淤滞 左心耳的栓子可引发栓塞 导致脑卒中或全身动脉栓塞 房颤 高血压与脑卒中 房颤房颤 高血压 Wolfetal Stroke1991 22 983 988 1 6的中风归因于房颤 FraminghamStudy 中国住院房颤病人抗血小板和抗凝治疗现状 阿司匹林 华发林 不用 房颤 中风危险分层 CHADS2 CHA2DS2 VASc LipGY HalperinJL AmJMed 2010 123 6 484 488 0 1 2 3 4 5 6 0 5 10 15 20 中风率 0 1 3 2 2 3 2 4 0 6 7 9 8 CHA2DS2 VASc积分 7 8 9 9 6 15 2 6 7 CHA2DS2 VASc积分与年中风率 HAS BLED出血危险积分 ESCAFGuidelinesEHJ2010 华法林抗凝作用 AF荟萃研究 Meta analysis 华法林 预防房颤缺血性脑卒中不可取代的药物 华法林 优点 INR评价抗凝强度多种拮抗药漏服一 二剂通常不会产生临床问题多年使用 经历了时间的考验维持目标INR的能力仍可提高价格便宜 华法林面临的问题 起效 停药可逆性慢剂量反应难于预测治疗剂量范围窄药物和食物相互反应监测麻烦高出血率 过量容易引起出血不足容易发生中风或肺栓塞量效曲线棘手 难以处理剂量调整主要靠反复监测 试试改改 华法林的使用 走钢丝 Fusteretal JAmCollCardiol 2001 38 1231 1266 缺血性中风与颅内出血 校正的OR与抗凝强度的关系 房颤应用华法林现状局限性导致治疗不足 SamsaGP etal ArchInternMed2000 160 967 INR超过目标6 未达到治疗剂量INR13 INR在目标范围15 无华法林65 房颤患者抗凝治疗一级预防的现状 治疗窗内时间TTR TimeinTherapeuticRange 口服华法林期间达到目标INR时间的百分比分析评价口服抗凝剂的疗效差异 SPORTIFIII和V华法林组与对照组患者结果事件差异TTR75 ArchInternMed 2007 WhiteHD GruberM FeyziJ KaatzS TseH HustedS AlbersG 研究中的新型抗凝剂 TFPI tifacogin Idraparinux RivaroxabanApixabanEndoxabanBetrixabanLY517717YM150TAK42 Dabigatran 口服 胃肠外 DX 9065aOtamixaban Xa IIa TF VIIa X IX IXa VIIIa Va II thrombin Fibrin Fibrinogen AT APC drotrecoginalfa sTM ART 123 AdaptedfromWeitzJI ThrombHaemost2007 5Suppl1 65 7 TTP889 APC活化蛋白CAT抗凝血酶sTM可溶性血栓调节素TF组织因子TFPI组织因子途径抑制物 5个新开发的药物 RuffCRandGiuglianoRP HotTopicsinCardiology2010 4 7 14ErickssonBIetal ClinPharmacokinet2009 48 1 22RuffCRetal AmHeartJ2010 160 635 41 CYP cytochromeP450 NR notreported 关于新型抗凝剂的试验 ARISTOTLE Apixaban 阿司匹林 RELY Dabigatran 华发林 ROCKET Rivaroxaban 华发林 ENGAGE Edoxaban 华法林 AVERROES Apixaban 华法林 与warfarin相比 AFIII期临床试验 Doseadjustedinpatientswith drugclearance Maxof10 withCHADS 2score 2andnostroke TIA SEEPROBE prospective randomized open label blindedendpointevaluationVKA VitaminKantagonist 为满足临床需要 针对AF卒中预防 临床已证实AF 卒中危险因素 是否有Warfarin适应症 RELY DabigatranROCKET RivaroxabanARISTOTLE ApixabanENGAGE Edoxaban AVERROES Apixaban No Yes Apixaban5mgBID ASA 81 324mg d AF合并 1危险因素 不适合服用VKA 主要终点 StrokeorSystemicEmbolicEvent SEE 5 600病人 AVERROES设计 2 5mgBID 在选择的病人 R 36个国家 522个中心 双盲 NEnglJMed2011 364 806 817 CumulativeRisk 0 0 0 01 0 03 0 05 0 3 6 9 12 18 21 ASA Apixaban No atRisk ASA Apix 2791 2720 2541 2124 1541 626 329 2809 2761 2567 2127 1523 617 353 Months RR 0 4695 CI 0 33 0 64p 0 001 StrokeorSystemicEmbolicEvent 54 MajorBleeding 与ASA比相似 ACTIVEA NEnglJMed2009 360 1 13HartRG etal AnnInternMed 2007 146 857 867AVERROES ESCHotline2010 NEnglJMed2011 364 806 817 从SPAF试验我们对使用抗血小板得到什么启发在AF与ASA抗栓治疗相比 Clopidogrel ASAVKAApixaban Favorstreatment FavorsASA 50 0 50 100 Relativeriskincrease 95 CI StrokeReductionIncreaseinIntracranialBleeding 28 38 54 87 128 15 100 AVERROES结论 对不适合VKA治疗 相对于ASA apixaban减少卒中 50 并不增加大出血与ASA相比 Apixaban可以很好耐受 尚没有肝毒性的证据对不适合VKA的房颤病人 apixaban有可能降低危险 从SPAF试验我们对使用抗血小板药物得到什么启发 summary 在预防AF卒中 对不适合华法林时 ASA仍然是目前仅有的替代药物 但仅是中等有效联合ASA和clopidogrel比ASA更有效 但仍不如warfarin有效 且可以引起出血增加在AVERROES试验 对较广范围的不适合warfarin的AF病人 Apixaban显示比ASA更有效 安全相似 更好耐受 为满足临床需要 针对AF卒中预防 临床已证实AF 卒中危险因素 是否有Warfarin适应症 RELY DabigatranROCKET RivaroxabanARISTOTLE ApixabanENGAGE Edoxaban AVERROES Apixaban No Yes RE LY 非劣效性检验设计 Open 房颤伴 1危险因素 没有禁忌症 患者来自44国家的951中心 华法林调整INR2 0 3 0N 6000 Dabigatranetexilate110mgBIDN 6000 Dabigatranetexilate150mgBIDN 6000 盲法结果判定 开放 双盲 R RE LY 中风或周围血管栓塞 0 50 0 75 1 00 1 25 1 50 Dabigatran110vs 华法林 Dabigatran150vs 华法林 非劣效性 p 值 0 001 0 001 优效性 p 值 0 34 0 001 Margin 1 46 HR 95 CI 华法林更好 Dabigatran更好 Connollyetal NEJM 2009 RR0 40 95 CI 0 27 0 60 p 0 001 sup RE LY 颅内出血 RR0 31 95 CI 0 20 0 47 p 0 001 sup Numberofevents 0 23 0 74 0 30 RRR69 RRR60 Connollyetal NEJM 2009 CammJ OralpresentationatESConAug30th2009 缺血性中风与周围血管栓塞荟萃分析 WvsplaceboWvsWlowdoseWvsASAWvsASA clopidogrelWvsdabigatran150 0 0 3 0 6 0 9 1 2 1 5 1 8 2 0 倾向华法林 倾向其他治疗 150mgBID MODERNERA RE LYStuartConnollyMD MichaelD EzekowitzMD SalimYusufMD Wallentin DabigatranversusWafarininPatientswithAtrialFibrillation NEJM2009 361 c NEJM2010 363 RE LY结论 与传统的华法林相比 达比加群两种剂量均显示出优势达比加群150mg更有效而达比加群110mg有更好的安全性两种有效剂量各有其优缺点 在临床上对不同特点的患者可做不同的治疗选择 Warfarin targetINR2 3 Apixaban5mgoraltwicedaily 2 5mgBIDinselectedpatients Primaryoutcome strokeorsystemicembolism Hierarchicaltesting non inferiorityforprimaryoutcome superiorityforprimaryoutcome majorbleeding death Randomizedoubleblind doubledummy n 18 201 InclusionriskfactorsAge 75yearsPriorstroke TIAorSEHForLVEF 40 DiabetesmellitusHypertension Warfarin warfarinplaceboadjustedbyINR shamINRbasedonencryptedpoint of caretestingdevice ExclusionMechanicalprostheticvalveSevererenalinsufficiencyNeedforaspirinplusthienopyridine AtrialFibrillationwithatLeastOneAdditionalRiskFactorforStroke ARISTOTLEMainTrialResults 21 RRR 31 RRR ISTHmajorbleeding Strokeorsystemicembolism MedianTTR66 Apixaban212patients 1 27 peryearWarfarin265patients 1 60 peryearHR0 79 95 CI 0 66 0 95 P 0 011 Apixaban327patients 2 13 peryearWarfarin462patients 3 09 peryearHR0 69 95 CI 0 60 0 80 P 0 001 Warfarin targetINR2 3 Apixaban5mgoraltwicedaily 2 5mgBIDinselectedpatients Primaryoutcome strokeorsystemicembolism Hierarchicaltesting non inferiorityforprimaryoutcome superiorityforprimaryoutcome majorbleeding death Randomizedoubleblind doubledummy n 18 201 InclusionriskfactorsAge 75yearsPriorstroke TIA orSEHForLVEF 40 DiabetesmellitusHypertension Warfarin warfarinplaceboadjustedbyINR shamINRbasedonencryptedpoint of caretestingdevice MajorexclusioncriteriaMechanicalprostheticvalveSevererenalinsufficiencyNeedforaspirinplusthienopyridine AtrialFibrillationwithatLeastOneAdditionalRiskFactorforStroke PrimaryOutcomeStroke ischemicorhemorrhagic orsystemicembolism Apixaban212patients 1 27 peryearWarfarin265patients 1 60 peryearHR0 79 95 CI 0 66 0 95 P superiority 0 011 No atRiskApixaban912087268440605134641754Warfarin908186208301597234051768 P non inferiority 0 001 21 RRR MajorBleedingISTHdefinition Apixaban327patients 2 13 peryearWarfarin462patients 3 09 peryearHR0 69 95 CI 0 60 0 80 P 0 001 No atRiskApixaban908881037564536530481515Warfarin905279107335519629561491 31 RRR MODERNERA ARISTOTLE Granger Alexander MacMurray Wallentin NEJM2011 ConnollySetalNEJM2009 PatelMetalNEJM2011 GrangerCetalNEJM2011 NewantithrombotictherapiescomparedtowarfarinStrokeorsystemicembolismDabigatran150mgb i d Dabigatran110mgb i d Rivaroxaban20mgo d Abixaban5mgb i d 0 5 1 2 NewantithrombotictherapiescomparedtowarfarinHemorrhagicstrokeDabigatran150mgb i d Dabigatran110mgb i d Rivaroxaban20mgo d Abixaban5mgb i d 0 1ConnollySetalNEJM2009 PatelMetalNEJM2011 GrangerCetalNEJM2011 1 2 ConnollySetalNEJM2009 PatelMetalNEJM2011 GrangerCetalNEJM2011 NewantithrombotictherapiescomparedtowarfarinStrokeofischemicorunknownoriginDabigatran150mgb i d Dabigatran110mgb i d Rivaroxaban20mgo d Abixaban5mgb i d 0 5 1 2 ConnollySetalNEJM2009 PatelMetalNEJM2011 GrangerCetalNEJM2011 NewantithrombotictherapiescomparedtowarfarinAll causemortalityDabigatran150mgb i d Dabigatran110mgb i d Rivaroxaban20mgo d Abixaban5mgb i d 0 5 1 2 ConnollySetalNEJM2009 PatelMetalNEJM2011 GrangerCetalNEJM2011 NewantithrombotictherapiescomparedtowarfarinMajorbleedingDabigatran150mgb i d Dabigatran110mgb i d Rivaroxaban20mgo d Abixaban5mgb i d 0 5 1 2 ConnollySetalNEJM2009 PatelMetalNEJM2011 GrangerCetalNEJM2011 NewantithrombotictherapiescomparedtowarfarinMajor clinicallyrelevantbleedingDabigatran150mgb i d Dabigatran110mgb i d Rivaroxaban20mgo d Abixaban5mgb i d 0 5 1 2 ConnollySetalNEJM2009 PatelMetalNEJM2011 GrangerCetalNEJM2011 NewantithrombotictherapiescomparedtowarfarinGastrointestinalbleedingDabigatran150mgb i d Dabigatran110mgb i d Rivaroxaban20mgo d Abixaban5mgb i d 0 5 1 2 NewantithrombotictherapiescomparedtowarfarinIntracranialhemorrhageDabigatran150mgb i d Dabigatran110mgb i d Rivaroxaban20mgo d Abixaban5mgb i d 0 1ConnollySetalNEJM2009 PatelMetalNEJM2011 GrangerCetalNEJM2011 1 2 ConnollySetalNEJM2009 PatelMetalNEJM2011 GrangerCetalNEJM2011 NewantithrombotictherapiescomparedtowarfarinMyocardialinfarctionDabigatran150mgb i d Dabigatran110mgb i d Rivaroxaban20mgo d Abixaban5mgb i d 0 5 1 2 NewanticoagulantscomparedtowarfarininAF2011 Effetonoutcomeevent D150D110Riva Apix NoninferioritystrokeReductionhemorrhagicstroke Reductionischemicstroke ReductionmortalityReductionmajorbleedingIncreasegastrointestinalbleeding IncreasemyocardialinfarctionFewertreatmentdiscontinuationsValidationinasecondrandomizedtrial ConnollySetalNEJM2009GrangerCetalNEJM2011 从SPAF试验我们对使用抗凝药物得到什么启发 summary Dabigatran rivaroxaban apixaban都提供比warfarin重要的优势 包括方便 至少有相似预防卒中的效果 少的颅内出血ARISTOTLE发现在预防卒中和系统性栓塞 使用单剂量的apixaban比warfarin有效 且发生出血减少 死亡率降低 期望新的药物对房颤病人提供改善机会 包括有适应症 但目前又未服用任何口服抗凝药物的病人 WarfarinRiskforstrokeandIntracranialbleeding ApixabanDabigatranRivaroxaban sideeffectse g otherbleedingsSurvivalPatientpreferencesHealtheconomy ThreenewanticoagulantssuperiortoWarfarinforpreventionofstrokeandintracranialbleedinginAFavailable2011 在2011年 与warfarin相比 Effetonoutcomeevent D150D110Riva Apix Strokeorsystemicembolism Noninferiority Reductionischemicstroke ReductionmortalityReductionmajorbleedingIncreasegastrointestinalbleeding IncreasemyocardialinfarctionFewertreatmentdiscontinuationsValidationinasecondrandomizedtrial ConnollySetalNEJM2009GrangerCetalNEJM2011 新抗凝剂Apixaban对房颤病人提供全面保护作用 Reductionhemorrhagicstroke Strokeorsystemicembolism superiority 谢谢 C MichaelGibson M S M D PatelMRetal NEJM2011 ConnollySJ etal NEnglJMed 2009 361 1139 1151 GrangerCetal NEngJMed 2011 3 86 ARISTOTLECOVERACROSSCHADS2SCORE 临床试验中TTR的情况 C MichaelGibson M S M D PatelMRetal NEJM2011 ConnollySJ etal NEnglJMed 2009 361 1139 1151 GrangerCetal NEngJMed 2011 Theinternationalnormalizedratio INR testisthelaboratorytestusedtodeterminethedegreetowhichthepatient scoagulationhasbeensuccessfullysuppressedbythevitaminKantagonist VKA Formostpatients thegoalistokeeptheINRbetween2and3 whichroughlycorrespondstothebloodtaking2to3timesaslongtoclotaswouldanormalperson sblood Thislevelofanticoagulationhasbeenshowntomaximizebenefit i e protectpatientsfrombloodclots whileminimizingrisk i e riskofhemorrhageattributabletoexcessiveanticoagulation TherapeuticINRrange TTR isawayofsummarizingINRcontrolovertime RE LYDabigatran110mg1 53 yrDabigatran150mg1 11 yrWarfarin1 69 yrROCKETAFRivaroxaban20mg2 1 yrWarfarin2 4 yrARISTOTLEApixaban5mg1 27 yrWarfarin1 60 yr 主要终点StrokeorSystemicEmbolism 非劣效性分析 p 0 001 p 0 001 p 0 001 NonInferiorirtypvswarfarin ITTAnalysis ModifiedITT NoITTanalysisisavailablefornon inferiorityinRocketAF Anontreatmentorper protocolanalysisisgenerallyperformedintheassessmentofnon inferiority Ifnumerouspatientscomeoffofstudydrug thisbiasesthetrialtowardsanon inferiorresultinanITTanalysis Thisisthebasisforperformingaper protocolanalysisinanon inferiorityassessment C MichaelGibson M S M D p 0 001 ITTAnalysis PatelMRetal NEJM2011 ConnollySJ etal NEnglJMed 2009 361 1139 1151 GrangerCetal NEngJMed 2011 HR 0 88 HR 0 79 HR 0 91 HR 0 66 superiority p 0 12 p 0 001 p 0 34 ITTAnalysis ModifiedITT P 0 01 ITTAnalysis 出血性卒中 Dabigatran110mg0 12 yr0 31 0 001Dabigatran150mg0 10 yr0 26 0 001Warfarin0 38 yr HR ITTP value Rivaroxaban20mg0 26 yr0 590 024 Warfarin0 44 yr ROCKET RELY C MichaelGibson M S M D InanontreatmentanalysisinRocketAFHemorrhagicStokerateswere0 26 yrforrivaroxabanand0 44 yrforwarfarin p 0 024 NoontreatmentanalysisisavailablefromRE LY Apixaban5mg0 24 yr0 51 0 001Warfarin0 47 yr ARISTOTLE PatelMRetal NEJM2011 ConnollySJ etal NEnglJMed 2009 361 1139 1151 GrangerCetal NEngJMed 2011 缺血性卒中 Dabigatran110mg1 34 yr1 110 35Dabigatran150mg0 92 yr0 760 03Warfarin1 20 yr HR ITTP value Rivaroxaban20mg1 62 yr0 990 92 Warfarin1 64 yr ROCKET RELY C MichaelGibson M S M D InanontreatmentanalysisinRocketAFIschemicStokerateswere1 34 yrforrivaroxabanand1 42 yrforwarfarin p 0 58 NoontreatmentanalysisisavailablefromRE LYandAristotle Aoixaban5mg0 97 yr0 920 42Warfarin1 05 yr ARISTOTLE PatelMRetal NEJM2011 ConnollySJ etal NEnglJMed 2009 361 1139 1151 GrangerCetal NEngJMed 2011 Dabigatran110mg2 71 yr0 80 003Dabigatran150mg3 11 yr0 930 31Warfarin3 36 150mgDabigatranvs110mgDabigatran HRof1 16 1 00 1 34 p 0 052 大出血MajorBleeding HR ITTP value RE LY Rivaroxaban20mg3 60 yr1 040 58 Warfarin3 4 yr ROCKET C MichaelGibson M S M D ThereisnoITTanalysisofsafetyinRocketAF ThereisnoontreatmentanalysisofsafetyfromRE LY OnTreatmentP value P value Apixaban5mg2 13 yr0 69 0 001Warfarin3 09 yr ARISTOTLE PatelMRetal NEJM2011 ConnollySJ etal NEnglJMed 2009 361 1139 1151 GrangerCetal NEngJMed 2011 2gdropin24hours 2gdrop AllCauseMortality Dabigatran110mg3 75 yr0 910 13Dabigatran150mg3 64 yr0 880 051Warfarin4 13 yr HR ITTp value Rivaroxaban20mg4 5 yr0 920 15 Warfarin4 9 yr ROCKET RELY C MichaelGibson M S M D InanontreatmentanalysisinRocketAFmortalityra